Pedigree Analysis

Basics

The genealogical analysis by a geneticist always happens when the desire to have a child arises in a family, but in the past, hereditary diseases have increased. With a genetic pedigree, the assessment and possible limitation of risks is possible. But first of all some basic knowledge:

Humans have a total of 46 chromosomes. Fertilization of egg and sperm cells turns two haploid (2 x 23) sets of maternal and male chromosomes into a diploid set of chromosomes (46). Accordingly, in each cell, apart from the germ cells, each chromosome is present in two variants. Once by the mother, and once by the father. One also speaks of homologous chromosomes (pairs of chromosomes 1 to 22), because they carry the same genes. An exception to this is the sex chromosomes (chromosome pair 23), also known by the technical term heterologous chromosomes (chromosome pair 23). They determine if we are genetically male (XY) or female (XX).

Whether certain hereditary diseases are pronounced or not depends on the stored gene information on the individual chromosomes. How and what leads to the individual characteristics will become clear during the course of this learning module.

Family tree analysis essentially involves two questions:

 1. Is the trait (hereditary disease) being traded via the autosomes (pairs of chromosomes 1 to 22) or the gonosomes (sex chromosomes XX or XY)?

 2. Is there a dominant or a recessive inheritance? In dominant inheritance, a dominant allele (either from the mother or father) is enough to develop the disease (Aa or AA). In the case of recessive heredity, on the other hand, both alleles must be identical (aa), so that it comes to the formation of characteristics.

This results in five different combinations of inheritance, all of which are explained below using an exemplary family tree.

 Autosomal dominant inheritance
 Autosomal recessive inheritance
 X-linked dominant inheritance (gonosomal)
 X-linked recessive inheritance (gonosomal)
 Y-chromosomal inheritance (gonosomal)

Basic vocabulary and visualization

Biological vocabulary for precise expression is essential. Therefore at the beginning standard vocabulary from classical genetics:

 Phenotype: external appearance of an organism. The appearance is always determined by the genotype. In the case of the pedigree analysis, the phenotype is synonymous with the severity of the disease of the particular heredity.

 Genotype: entire genetic makeup of an organism. For the pedigree analysis, only two corresponding homologous chromosomes are considered per inheritance, which are responsible for the severity of the disease. In the case of autosomal inheritance, the variables A and a (representative of dominant and recessive), in gonosomal inheritance the variables X and Y (representative of the chromosomes) are used.

 Allele: refers to the different variants / characteristics of a feature or gene

 Recessive feature: is represented within the pedigree analysis with the variable "a".

 Dominant characteristic: is represented within the family tree analysis with the variable "A".

 Homozygous: both alleles are identical (either AA or aa)

 Heterozygous: both alleles are different (e.g., Aa)

Family trees are visualized uniformly:

 Circle (with color) = woman (with hereditary disease)
 Square (with color) = man (with hereditary disease)
 Circle with dot = conductor (transmitter)

Autosomal dominant inheritance

For the expression of the characteristic in an autosomal dominant inheritance, at least one dominant allele (A) must appear in the genotype.

(1) and (2) are homozygous or heterozygous for the corresponding trait, so they are both ill. Your children (5) and (6) can only be trait carriers because of the mother (1). It always inherits at least one dominant allele, so the genotype of the father does not matter.

On the other hand, the children of (3) and (4) can be quite healthy, since the mother (3) has two healthy alleles, and the father (4) has a healthy allele. As long as the dominant allele of the father (4) is left out, healthy children will always be homozygous (aa -> 7 & 9) and sick heterozygotes (Aa -> 8). Within an autosomal dominant inheritance, all healthy persons are genotypically always definable with (aa)! Consequently, the children of the parents (9) and (10) are invariably healthy, for if no parent possesses the trait, it can not be inherited.

In the descendants of (6) and (7), chance again determines whether or not they are carriers of meaning. Either the father (6) inherits the dominant gene or the recessive gene. In the first case the child is ill (11), in the second case homozygous healthy (12).

What indicates an autosomal dominant inheritance?

 * Almost every generation has feature carriers
 * Women and men are affected in similar proportions
 * If a child is positive for the trait, it is also a parent

Examples of Autosomal Dominant Genes: 

Huntington's Disease, Marfan Syndrome, Neurofibromatosis, Polydactyly (Multiple Fingering)

Autosomal recessive inheritance

In order for a characteristic expression to occur in an autosomal recessive inheritance, both recessive alleles must be homozygous (aa).

Mother (1) and father (2) are phenotypically healthy. Nevertheless, they both carry the recessive (a) allele. Their offspring only become ill if they inherit the recessive gene from both parts of the elves (6). As long as at least one dominant gene, either from mother or father, is inherited, the child is phenotypically healthy (5).

In direct progeny of (3) and (4), hereditary disease will not occur without exception. Because the genotype of the mother (3) proves to be homozygous healthy, so that in the genotype of children always at least one (A) will be present.

Both the parents (6) and (7), as well as (8) and (9), the risk of further transmission. The probability of this is higher in (6) and (7), because mother (6) will, in contrast to father (8), in any case pass on a recessive allele. In (8) there is still the possibility of further transmission of the dominant allele (A).

What indicates an autosomal recessive inheritance?

 * Not every generation has feature carriers
 * Women and men are affected in similar proportions
 * Parents can be healthy while their children are charity carriers

Examples of autosomal recessive inheritance:

Albinism, cystic fibrosis, cretinism, sickle cell disease

X-linked dominant inheritance (gonosomal)

In contrast to autosomal inheritance, the characteristics of gonosomal inheritance are inherited via the sex chromosome. Therefore, as variables, the chromosomes X (dominant), x (recessive), and Y (in this inheritance in the case of inheritance without meaning) are conveniently used directly.

Due to the fact that males have only one X chromosome, their genotype is always unique in X-linked dominant inheritance. Either they have a recessive allele and are healthy (xY), or they have a dominant allele and are ill (XY).

The daughters of a father with characteristic expression will phenotypically always form the disease, because they get in each case the dominant X chromosome. In the family tree this is recognizable to father (7) and his daughters (10) and (11).

In the case of the heterozygous mother (1) and the healthy father (2), the randomness of the chromosome distribution once again determines whether or not the characteristic expression occurs (5 and 7) or not (6). Accordingly, even phenotypically healthy daughters are always genotypically determinable (xx).

Parents (3) and (4), however, are insignificant for hereditary disease. As with autosomal dominant inheritance, non-inherited traits can not be inherited.

What indicates an X-gonosomal dominant inheritance?

* In almost every generation there are feature carriers
* Women and men are affected, the former usually more often
* If the father is the attribute bearer, so are all his daughters as well

Examples of X-gonosomal dominant inheritance:

Alport syndrome, vitamin D-resistant rickets

X-linked recessive inheritance (gonosomal)

As with X-linked dominant inheritance, in the case of X-linked recessive inheritance, men are always clearly diagnosed in terms of their genotype and phenotype. Either they have a recessive allele and are ill (xY), or have a dominant allele and are healthy (xy). Within this mode of inheritance, women function as a conduit, therefore they transmit the recessive allele (x) without being affected by hereditary disease itself (xx). In contrast to men, women can compensate for the recessive (diseased) gene by a dominant (healthy) gene, which does not lead to the expression of the trait. Therefore, significantly more men are affected in X-linked recessive inheritance.

In the present pedigree, (1), (3) and (6) are conductors of the hereditary disease. Chance again decides the chromosomal distribution of offspring. Because of their dominant allele (regardless of the genotype of the father) both healthy (8) and sick (10,11) children are possible. There is only a difference in terms of the probability of the characteristic being pronounced, for a healthy father (7), in contrast to a sick father (4), only inherits dominant alleles (which prevent one expression).

But women can also get sick (9). Namely, when the mother is the conductor (3), and the father (4) is the carrier of the hereditary disease.

What indicates an X-gonosomal-recessive inheritance?

* For the most part, men are the carriers of meaning

* Women as Conductors, without being affected

* Women are affected only when father is affected and mother is a conductor

Examples of X-gonosomal recessive inheritance:

Hemophilia (hemophilia), red-green-blindness

Y-linked dominant inheritance (gonosomal)

For the sake of completeness, mention should also be made of Y-linked dominant inheritance. As already noticed in the pedigree, only men are affected and that has a simple reason: women "lacks" the Y-chromosome. Therefore, there is only one single rule in trait inheritance in this mode of inheritance: men always pass on the Y chromosome to their sons.

The Y chromosome is mainly responsible for the development of the male phenotype, but has hardly any other genetic material itself, which is why the existence of this inheritance is by no means certain.

What indicates a Y-gonosomal dominant inheritance?

* Only men are the attribute carriers

* If the father is affected, his sons are invariably too

* Women are neither affected nor a conductor

Summary

The pedigree analysis is suitable for diagnosis and risk assessment in the inheritance of hereditary diseases.

A distinction is made between dominant and recessive inheritance, as well as autosomal and gonosomal inheritance.

Overall, there are five different inheritance types with autosomal dominant, autosomal recessive, gonosomal dominant, gonosomal recessive and y chromosomal, of which the latter is not proven.